This application is based on European Patent Application No. 01830413.9 filed on Jun. 21, 2001, the content of which is incorporated hereinto by reference.
The present invention relates to 4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide (formula 1 in FIG. 1) as a pharmacologically active compound in the treatment of vascular diseases.
More particularly, this invention relates to 4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide as well as the acid addition salts thereof with pharmaceutically acceptable organic or inorganic acids as pharmacologically active compounds in the treatment of atherosclerotic-thrombotic pathological conditions and other pathological conditions which can benefit from the inhibition of thromboxane A2 and from a pharmacological supply of nitric oxide (NO).
The invention also relates to processes for the preparation of 4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide and the acid addition salts thereof with pharmaceutically acceptable organic or inorganic acids.
Furthermore, the invention relates to a pharmaceutical composition comprising 4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide or an acid addition salt thereof with pharmaceutically acceptable organic or inorganic acids, as an active ingredient, together with at least a pharmaceutically acceptable ingredient.
The invention also relates to a method of use of both said compound and said pharmaceutical composition in the treatment of said conditions.
Evidence is growing for a dynamic interplay between the processes of thrombosis and atherosclerosis in the vascular system, starting from the initial development of vascular diseases and continuing in the dramatic events that are the cause of death and disability in a large section of the population. Diabetes, hypertension, tobacco smoke and unhealthy dietary habits are among the leading causes of these diseases.
Blood and vascular wall exert mutual influences in their physiological functions, which are mediated by the contact of blood cells (including platelets, which differ from other cells by lacking the cellular nucleus) with the vascular endothelial and smooth muscular cells, via mechanisms of adhesion and infiltration, and by the exchange of a number of biochemical mediators.
Most of these interactions are also involved in pathological processes, such as the development of acute vasospastic conditions, the formation of occlusive thrombi and the development of atherosclerotic plaques.
The role played by activated platelets has special relevance, since the present advancement of knowledge indicates that the pro-thrombotic and pro-atherogenic role of platelet activation is not limited to the initiation of the formation of thrombi starting from platelet aggregates, but it involves adhesion and the mutual interchange of biochemical mediators with the vascular wall, especially when the latter is pathologically altered, as in the case of endothelial lesions and of atherosclerotic plaques (R Ross, NE J Med 340 (1999) 115-126; B Osterud, Thromb Res 85 (1997) 1-22).
Platelet-released mediators have a role in vasospasms, a critical mechanism of various ischemic conditions, and in the proliferation of vascular smooth muscle, an essential step of the atherosclerotic process (AA Weber, K Schror, Thromb Haemost 80 (1998) 207-208; T Grosser et al, Eur J Pharmacol 319 (1997) 327-332; R Pakala et al, Circulation 96 (1997) 2280-2286; A Sachinidis et al, Hypertension 26 (1995) 771-780), which in turn, by the alteration of the vascular surface and the rupture of plaques contributes to platelet activation and has an immediate causative role in acute thrombotic and ischemic events.
Among the mediators released by platelets, thromboxane A2, serotonin, and growth factors, such as PDGF and TGF-xcex21 are the most pathologically relevant.
On the other hand, the endothelial lining of the vascular wall, when not pathologically altered, opposes the actions of activated platelets by the release of mediators (DA Jones et at, Mol Pharmacol 48 (1995) 890-896; PM Vanhoutte, JV Mombouli, Progress in Cardiovascular Diseases 39 (1996) 229-238) such as EDRF (the endothelial derived relaxing factor, identified as NO, nitric oxide), and as prostacyclin. Both induce relaxation and reduce proliferation of the arterial wall, and counteract platelet aggregation and adhesion (U Forstermann et al, Circulation Res 63 (1988) 306-312; MW Radomski et al, Br J Pharmacol 92 (1987) 639-646).
Cellular interactions of platelets, blood cells, and vascular cells have special relevance in the synthesis of a cascade of metabolites of arachidonic acid, the eicosanoids (J Macloufet al, Thromb Haemost. 79 (1998) 691-705). Arachidonic acid is converted by the enzymatic action of the cyclooxygenases, into the endoperoxides PGG2 and PGH2. These metabolites are further converted into thromboxane A2 and into prostacyclin PGI2, as wells as into PGE2, PGD2 and other prostaglandins, by the enzymatic action of specific synthetases.
Owing to the different cellular locations of these enzymes, the transcellular exchange of the precursor arachidonic acid (which is also carried by fragmented platelets) and, most importantly, of the endoperoxides PGG2 and PGH2 exerts significant influence in the generation of the biologically active eicosanoids, and among them thromboxane A2 and prostacyclin. Important amount of endoperoxides are formed in platelet and in endothelial cells under the influence of cyclooxygenase-1. These amount predominate in normal conditions, over those produced in other cells, such as lymphocytes (including the monocyte-macrophage type) and vascular smooth muscle cells.
The synthesis of endoperoxides can however be amplified, in pathological situations, by the induction, in all the above cells, but not in platelets, of the formation of large amounts of cyclooxygenase-2. The induction is mediated by pro-inflammatory stimuli, and is marked in atherosclerosis-damaged tissues (JA Rimarachin et al, Arterioscler Thromb 14 (1994) 1021-1031; D Bishop-Bailey et al, ibid, 18 (1998) 1655-1661). It has to be noted that eicosanoids generation, via cyclooxygenase-1 and/or cyclooxygenase-2 has important physiological and pathological roles, in addition to those elicited within the circulatory system, in various body organs.
According to their respective physiological role, platelets are abundantly endowed with thromboxane synthetase, as endothelial cells are with prostacyclin synthetase.
Thromboxane A2, acting as an inducer of irreversible platelet aggregation and also representing an amplifying signal of platelet activation, has a key role in platelet-vascular wall interactions not only because of its direct action, but also for the stimulation of the release of the other vasospastic and proliferative mediators generated by platelets and for the progression of the fissuring of atherosclerotic plaques, leading to occlusive vascular events.
The efforts of developing clinical applications of drugs acting by inhibition of thromboxane A2 have been enacted by different approaches. The first therapeutic approach directed to the inhibition of the synthesis of thromboxane A2 has been based on the use of acetylsalicylic acid, which is now known to be able to inhibit cyclooxygenase-1 selectively and irreversibly; the therapeutic usefulness has been clinically demonstrated, but the blockade of the first, common step of the synthesis of the eicosanoids brings together the inhibition the synthesis of physiologically beneficial prostaglandins in the circulatory system, in particular prostacyclin, and also of prostaglandins performing a protective role in gastric and renal tissues by maintaining perfusion and cytoprotection.
The benefit of this pharmacological approach is thus limited by undesirable effects. Furthermore, acetylsalicylic acid proved to be unable to inhibit the inducible cyclooxygenase-2, therefore leaving an open way to the productions of thromboxane A2 in inflamed tissues of the circulatory and respiratory system and in other body organs.
A second pharmacological approach has been targeted to the suppression of the synthesis of thromboxane A2 by specific inhibition of thromboxane synthetase, without hindering the synthesis of the other eicosanoids, and in particular prostacyclin (J Nowak, GA FitzGerald, J Clin Invest 83 (1989) 380-385).
Furthermore, a third approach has been also explored, not aimed at inhibiting the synthesis of thromboxane, but at hindering its effect on platelets and on vascular tissue by using agents able to exert an antagonistic action at thromboxane receptors (TP receptors).
These latter two approaches (J Vermylen, H Deckmyn, Cardiovascular Drugs and Therapy, 6 (1992) 29-33) have led to a number of clinical studies, but have not yet offered a valid alternative to the use of acetylsalicylic acid.
It has been reasoned that competitive antagonists are probably not adequate to fully antagonize the large amount of thromboxane A2 produced by aggregating platelets, while on the other hand, during thromboxane synthetase inhibition at the endoperoxide stage, the increased concentrations of intermediate endoperoxides exerted on tromboxane receptors effects similar to those of thromboxane itself. Therefore, the possible benefits of the combination of these two pharmacological approaches in single pharmacological agents exerting a dual action, such as picotamide (4-methoxy-N1,N3-bis-(3-pyridinylmethyl)-1,3-benzenedicarboxide) or ridogrel (5-[3-pyridinyl-3-(trifluoromethyl) phenylmethyleneaminooxy]pentanoic acid), have also been suggested (P Gresele et al, Trends Pharmacol Sci 12 (1991) 158-163).
In conclusion, the proposed pharmacological agents addressed to the direct inhibition of thromboxane have not yet reached general acceptance in medical practice, and only acetylsalicylic acid has an established and consolidated use as an antithrombotic agent, notwithstanding its limitations and unwanted effects.
Organic nitrates, such as nitroglycerin or isosorbide mono and dinitrate, have a well established clinical use, which is however confined to the exploitation of their vasodilator properties. In recent years, a better understanding of the pharmacological action of various precursors of NO on platelets and on the vascular wall has been achieved, following the identification of EDRF (endothelium derived relaxing factor) as nitric oxide, NO, and the clarification of its physiological role. This advancement of knowledge has been applied both to organic nitrates, and to new NO-donors, carrying nitrate or nitrite functions, or other chemical function easily converted to NO, and also to the biochemical precursor of endogenous NO, L-arginine. The advancement has led to the suggestion that, in addition to their known vasodilator action, the NO-donors may interact with pharmacological agents acting on the cascade of the metabolites of arachidonic acid, either in counteracting stimuli of platelet activation, vasoconstriction, and vascular cell proliferation (M Emerson et al, Thromb Haemost 81 (1999) 961-966; E Bassenge, Basic Res Cardiol 86 (suppl 2, 1990) 69-76), or by a direct modulation of the synthesis of eicosanoids (D Salvemini et al, J Clin Invest 97 (1996) 2562-2568).
Therefore a strong medical need still exists of increasedly effective antithromboxane agents for the prevention and the therapy of vascular atherosclerotic-thrombotic diseases and of other pathological conditions. The inventors perceived that more favourable therapeutic effects can be achieved by decreasing the synthesis of thromboxane A2, while at the same time inhibiting its actions, and also pharmacologically supplying nitric oxide.
It is therefore an object of this invention to provide a compound useful in the treatment of vascular diseases.
It is another object of this invention to provide a compound useful in the treatment of atherosclerotic-thrombotic pathological conditions.
It is yet another object of this invention to provide a compound having both antithromboxane and NO-donor action.
It is a further object of this invention to provide processes for the preparation of the compound having the above mentioned properties.
It is still another object of this invention to provide a pharmaceutical composition comprising the compound having the above mentioned properties as an active ingredient together with at least a pharmaceutically acceptable ingredient.
It is a further object of this invention to provide a method of treatment comprising administering to a human being suffering from a vascular pathological condition, such as atherosclerotic-thrombotic diseases, and of other conditions which can benefit from inhibition of thromboxane A2 and from a pharmacological supply of nitric oxide, an effective amount of a compound having the above mentioned properties.
These and other objects of the invention are achieved by 4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide and the acid addition salts thereof with pharmaceutically acceptable organic or inorganic acids.